Ionic channels in nerve and muscle are discrete molecular sites which control ionic permeability, and are the membrane proteins most directly related to membrane physiological properties. The objectives of this project are (1) to study the molecular mechanisms of sodium channels; (2) to study molecular regulation of membrane excitability in cells; and (3) to relate these findings to pathophysiology of function in excitable membranes in disease states. The proposed work: (1) studies properties of mammalian myelinated and demyelinated nerve, by studying control of ionic channel distribution in myelinated nerve using exchange-labelled saxitoxin; and by studying special properties of excitability in mammalian nerve, by voltage clamp studies of mammalian nodes of Ranvier; (2) studies sodium channel development in normal and abnormal mouse cerebellum correlating findings in vivo with those in tissue culture; (3) studies properties of the cardiac sodium channel ionophore; (4) studies the action of alkaloid and polypeptide neurotoxins, to localize the molecular sites of action of these toxins by voltage clamp techniques, and studying synthetic modifications of these toxins which retain activity; (5) studies the factors leading to development of excitability in cells and the average lifetime of the sodium channel in tissue culture preparations.